Rapamycin is a macrocylic triene antibiotic produced by Streptomyces hygroscopicus, which was found to have antifungal activity, particularly against Candida albicans, both in in vitro and in vivo C. Vezina et al., J. Antibiot. 28, 721 (1975); S. N. Seghal et al., J. Antibiot. 28, 727 (1975); H. A. Baker et al., J. Antibiot. 31, 539 (1978); U.S. Pat. No. 3,929,992; and U.S. Pat. No. 3,993,749!. ##STR2##
Rapamycin alone (U.S. Pat. No. 4,885,171) or in combination with picibanil (U.S. Pat. No. 4,401,653) has been shown to have antitumor activity. R. Martel et al. Can. J. Physiol. Pharmacol. 55, 48 (1977)! disclosed that rapamycin is effective in the experimental allergic encephalomyelitis model, a model for multiple sclerosis; in the adjuvant arthritis model, a model for rheumatoid arthrtis; and effectively inhibited the formation of IgE-like antibodies.
The immunosuppressive effects of rapamycin have been disclosed in FASEB 3, 3411 (1989). Rapamycin has been shown to be effective in inhibiting transplant rejection (U.S. Pat. No. 5,100,899). Cyclosporin A and FK-506, other macyclic molecules, also have been shown to be effective as immunosuppressive agents, therefore useful in preventing transplant rejection FASEB 3, 3411 (1989); FASEB 3, 5256 (1989); and R. Y. Calne et al., Lancet 1183 (1978)!. U.S. Pat. No. 5,321,009 discloses a method of prophylactically preventing the onset, preventing the development, and arresting the progression of insulin-dependent diabetes mellitus by administration of rapamycin. U.S. Pat. No. 5,288,711 discloses a method of preventing or treating hypeoliferative vascular disease by administration of a combination of rapamycin and heparin. U.S. Pat. No. 5,286,730 discloses a method of treating inummointlammatory disease by treatment with rapamycin alone or in combination with cyclosporin A. U.S. Pat. No. 5,286,731 provides a method of treating immunoinflammatory bowel disease by administration of rapamycin alone or in combination with cyclosporin A.
Various structural features of rapamycin have been modified in efforts to increase the potency or specificity of pharmacological action. For instance, a number of U.S. patents disclose compounds where one or more of the hydroxy groups having normal stereochemistry at positions 14, 31, and 42 have been converted into acyl esters, sulfonyl esters, and carbamates. U.S. Pat. No. 5,023,263 discloses 42-oxo rapamycin. U.S. Pat. No. 5,258,389 discloses 31 and/or 42 O-alkyl, O-aryl, O-alkenyl, and O-alkynyl ethers of rapamycin having nomal stereochemistry at the 42 position. The PCI published application WO 94/09010 discloses 31 and/or 42 O-alkylated rapamycin analogs wherein the keto groups at positions 15 and 33 may be reduced to a hydroxyl group or a methylene group.